Influence of laparoscopic surgery for endometriosis and its recurrence on perinatal outcomes

Abstract Purpose It is unknown whether surgery for endometriosis or recurrence of endometriosis affects obstetric outcomes. Methods A total of 208 pregnant women with a history of endometriosis were analyzed. Patients who had endometriomas >3 cm and no history of laparoscopic surgery for endometriosis were defined as non‐surgery group (n = 60), while those who had a history of surgery for endometriosis (n = 148) were defined as surgery group. We investigated the obstetric outcomes in 208 patients according to with or without postoperative recurrence of endometriosis and the time from surgery to pregnancy. Results Among 177 cases of on‐going pregnancy, in surgery group, there were lower prevalence of placenta previa compared with non‐surgery group (8.5% vs. 23.4%; p = 0.020). Subgroup analysis revealed a decreased prevalence of placenta previa in postoperative non‐recurrence group (6.0%: p = 0.007) compared with non‐surgery (23.4%) and postoperative recurrence group (28.6%). Placenta previa was more prevalent in the patients who got pregnant more than 2 years after surgery (20.0%) than the patients who got pregnant within 2 years (2.4%: p = 0.002). Multivariate analysis revealed that the surgery was associated with a reduction in placenta previa (OR: 0.32, 95% CI [0.11–0.90]; p = 0.032). Conclusions Pregnancy within two years after laparoscopic surgery for endometriosis may reduce placenta previa.

(SGA), and placental abruption. [8][9][10][11][12][13] Although surgical interventions for endometriosis, such as laparoscopic cystectomy, excision, ablation, and adhesiolysis, are performed when conservative treatments are ineffective, the influence of surgery on perinatal outcomes is still not fully understood. 14 Several studies have examined the effect of surgery for endometriosis on perinatal prognosis. Innie et al. 15 reported that women who underwent surgical treatment for endometriosis before pregnancy were found to have an elevated risk of placenta previa compared with those without endometriosis. Lin et al. 16 reported that pregnant women with surgically diagnosed endometriosis have a higher risk for placenta previa, preterm delivery, fetal growth restriction (FGR), and cesarean delivery, even after adjustment for the impact of assisted reproductive technology (ART), compared to patients with normal pregnancy. These reports all compared obstetric complications between patients who underwent surgery for endometriosis before pregnancy and pregnant patients without endometriosis. However, so far, few studies have compared the perinatal prognosis between those who have endometriosis during pregnancy and those who have undergone surgery for endometriosis before pregnancy.
In this study, we retrospectively investigated whether a history of surgical treatment for endometriosis affects perinatal outcomes by comparing pregnant women with endometriosis, and no history of surgical treatment to pregnant women who underwent surgery for endometriosis before pregnancy.

| ME THODS
The Institutional Review Board of three institutions approved this study (2- The requirement for obtaining written informed consent was waived because of the retrospective nature of the study. This retrospective study was carried out to evaluate the perinatal outcomes of pregnant patients with endometriosis between January 1, 2005, and December 31, 2019, in three institutions. This study was conducted by collecting as much data as possible from 15 years ago, when endoscopic surgery for endometriosis could be performed stably at the research facilities. Endometriosis was diagnosed by pathological examination, transvaginal ultrasonography, and/or magnetic resonance imaging. Pregnant patients with current endometriosis or a history of endometriosis were included. Few previous studies have defined the severity of endometriosis and examined the perinatal prognosis. A recent review shows that severe endometriosis and non-severe endometriosis have different effects on the obstetric outcome such as placenta previa. 17 Therefore, in this study, patients with severe endometriosis, which is easily diagnosed by imaging studies, were included in the study. And ovarian endometrioma was defined as having >3 cm diameter, according to the highest stage of ovarian lesions in the revised American Society for Reproductive Medicine (re-ASRM) classification. In the present study, we focused on how surgery for endometriosis affects the obstetric complications; therefore, we set the group that did not undergo surgery as the control group. The non-surgery group comprised pregnant patients with ovarian endometrioma at the time a gestational sac was confirmed by transvaginal ultrasound. The surgery group included pregnant patients who had a history of laparoscopic surgery for endometriosis, with or without recurrence during pregnancy. Surgical treatments, such as laparoscopic cystectomy, excision, ablation, and/or adhesiolysis, were performed at any of the three institutions.
We investigated the perinatal prognoses of the two groups. In addition, in subgroup analysis, we compared the perinatal outcomes of the non-recurrent group, in which the absence of recurrence of endometrioma was confirmed by transvaginal ultrasound in early pregnancy, and the recurrent group, in which endometrioma was present in early pregnancy. The recurrence of endometriosis was also defined as having an endometrioma >3 cm in diameter.
In general, a flare-up of endometriosis symptoms within 2 years postoperatively is reported in 50% of patients with endometriosis 18 and in 40%-80% of patients with endometriosis according to the American College of Obstetricians and Gynecologists guidelines. 19 Therefore, we divided the surgery group into pregnant women for whom the time from surgery to pregnancy was within 2 years (<2Y group) and more than 2 years (>2Y group), regardless of the sign of the recurrence, and we compared the perinatal outcomes of the <2Y and >2Y groups. The patients' clinical data were collected from the electronic medical records. Maternal characteristics included maternal age, body mass index before pregnancy, parity, the prevalence of leiomyoma, unilateral or bilateral of ovarian endometrioma, and the history of surgery for uterus and ART. ART included in vitro fertilization and intracytoplasmic sperm injection. Maternal outcomes included miscarriage (delivery before 22 gestational weeks), preterm labor (<37 gestational weeks), placenta previa, HDP, FGR, gestational diabetes mellitus (GDM), oligohydramnios, placental abruption, delivery mode, and the amount of blood loss at delivery. Neonatal outcomes included gestational age, birth weight, SGA, umbilical artery pH, and Apgar scores at 1 and 5 min. We excluded women with multiple pregnancies, congenital abnormalities, chronic hypertension or diabetes mellitus, endocrine diseases, cardiovascular diseases, and other internal complications.
The clinical data were analyzed using JMP version 10 (SAS Institute Inc.). In the comparison between the two groups, statistical analysis was performed using the Mann-Whitney U test, Fisher's exact test, and chi-square test. For the comparison between the three groups, the analysis was performed by using the ANOVA test and the chi-square test by m × n contingency table. The statistical significance was set at p < 0.05.

| Non-surgery group vs. surgery group
A total of 208 pregnant women with endometriosis were enrolled in this study. The non-surgery group included 60 pregnancies with ovarian endometrioma and no history of surgical treatment, and the surgery group included 148 pregnancies after laparoscopic surgery for endometriosis.
Maternal characteristics are shown in Table 1. There were no differences in age, body mass index, parity, and ART pregnancy rate, the percentage of bilateral ovarian endometrioma, leiomyoma, and the history of surgery for uterus between the two groups. In the non-surgery group, the ovarian endometrioma diameter was 45.5 ± 16.4 mm (mean ± standard deviation) in the early pregnancy period. In the surgery group, the preoperative ovarian endometrioma diameter was 47.3 ± 15.5 mm, and the re-ASRM score was 57.8 ± 61.6 points. The mean period from surgery to subsequent pregnancy was 29.3 ± 30.4 months.
There was one case of apparent rupture of endometrioma during pregnancy in the non-surgery group, but it did not result in emergent surgery. The rupture case of endometrioma was not confirmed in the surgery group. There were no differences in the mean gestational age, birth weight, umbilical artery pH, amount of blood loss at delivery, and Apgar scores at 1 and 5 min between both groups (Table 1).

| Surgery group: Non-recurrence vs. recurrence
To examine the influence of recurrent endometrioma on perinatal prognosis, we sub-categorized the surgery group into those TA B L E 1 Maternal characteristics and perinatal outcomes of patients with endometriosis between the non-surgery and surgery groups  with postoperative non-recurrence of endometrioma >3 cm and those with postoperative recurrence. There were no differences in patient background between the non-surgery, postoperative non-recurrence, and postoperative recurrence groups (Table 2).
There was no significant difference in the mean preoperative ovarian endometrioma diameter, the mean re-ASRM score, and the mean period from surgery to subsequent pregnancy, miscarriage, and the percentage of bilateral ovarian endometrioma between the non-recurrence and recurrence groups. The prevalence of leiomyoma tended to be lower in the postoperative recurrence group (p = 0.091), and the percentage of surgical history for uterus tended to be higher in the postoperative recurrence group among the three groups (p = 0.051) (

| Surgery group: <2 years vs. >2 years after surgery
To investigate the influence of not only ovarian endometrioma but also endometriosis recurrence as a whole on perinatal outcomes, we stratified the surgery group into the <2Y and >2Y groups. We compared the perinatal outcomes of the non-surgery group, the <2Y group, and the >2Y group.
There rate of ART tended to be higher in <2Y group (p = 0.059) and the percentage of the surgical history for uterus tended to be higher in >2Y group (p = 0.062) among the three groups.
There were no differences in the other clinical backgrounds among the three groups. The recurrence rate of endometrioma was significantly higher in the >2Y group (24.0%, 12/50) than in the <2Y group (4.1%, 4/98; p = 0.001, Table 3). The prevalence of placenta previa was lower in the <2Y group among the three groups To investigate which factors were associated with the prevalence risk of placenta previa, we performed a logistic regression analysis and found that history of laparoscopic surgery for endometriosis (odds ratio, OR: 0.32, 95% confidential interval, CI (0.11-0.90); p = 0.032) was associated with a reduced risk of placenta previa.
In the surgery group, multivariate analysis showed that pregnancy more than 2 years after surgery for endometriosis (OR: 7.98, 95% CI

F I G U R E 1 (A and B) Bar graphs illustrating perinatal outcomes in pregnant patients with endometriosis and no surgery, with
postoperative non-recurrence of endometrioma, and with postoperative recurrence of endometrioma Data are presented as mean ± standard deviation or as n (%). FGR, fetal growth restriction; GDM, gestational diabetes mellitus; HDP, hypertensive disorders of pregnancy; N.S., not significant; SGA, small for gestational age. p-values < 0.05 are considered statistically significant prevalence of placenta previa; 20 however, there was no association between ART and placenta previa in this study (Table 4).

| DISCUSS ION
This study aimed to investigate the effect of laparoscopic surgery for endometriosis on perinatal outcomes in subsequent pregnancies.
In recent years, much attention has been focused on the association between endometriosis and perinatal outcomes, such as miscarriage, placenta previa, preterm premature rupture of membranes, preterm birth, HDP, SGA, postpartum hemorrhage, placental abruption, stillbirth, and neonatal death. [8][9][10][11][12][13]15,21  showed that gynecological surgery for endometriosis before pregnancy did not improve perinatal outcomes. Contrary to their results, in the present study, a significant decrease in the prevalence of placenta previa was found in the surgery group compared with that of the non-surgery group with endometriosis. In the previous papers, the authors pointed out the limitation that the time from surgery to pregnancy and the severity of endometriosis in the target patients were not clear. 28,29 These may have contributed to the difference between our results and theirs. A recent systematic review shows that severe endometriosis is associated with an increased prevalence of placenta previa, whereas non-severe endometriosis was not. 17 Therefore, in the present study, we determined the definition of endometriosis patients with endometriomas >3 cm in diameter, that is, only those with r-ASRM classifications of stage III or IV. This  This study has several limitations. First, in the non-surgery group, endometriosis was diagnosed based on ultrasonography and/ or MRI, which are less reliable than the reference standard laparoscopy. Second, although the size of ovarian endometrioma was not different between the surgery and non-surgery groups, there may be a difference in the severity of endometriosis between the two groups, since pelvic endometriosis cannot be assessed by imaging, and this may affect the prevalence of placenta previa. Third, this was a retrospective study, and the sample size was smaller than those in previous studies. 28,29 Fourth, as the medical treatments for endometriosis, especially hormonal treatments, have changed over the 15-year period, we cannot deny that these effects may have affected the patient outcome. Fifth, since we could not examine how the intra-peritoneal environment and general condition of the patient changed postoperatively, the mechanism of improvement in perinatal prognosis is not fully understood.
In conclusion, laparoscopic surgery for endometriosis may decrease the prevalence of placenta previa in the subsequent pregnancy. However, since the prevalence risk of placenta previa may be re-increased if more than two years have passed from the surgery to pregnancy, it may be better to recommend to conceive within two years. Further prospective studies are needed in the future.

ACK N OWLED G EM ENT
The authors express the deepest gratitude to Dr. Masatoshi Sakai for his best support.

TA B L E 4
Logistic regression analysis of the factors related to the prevalence of placenta previa in the patients with endometriosis and the endometriosis patients with a history of surgery Note: Data are presented as odds ratio (95% Confidential Interval). P-values < 0.05 are considered statistically significant.

D I SCLOS U R E S
We have no conflict of interest to disclose. This study was approved by the hospital's ethics committee and has been approved by the IRB. We are in compliance with the Statement of Human Rights.
Because this is a non-invasive retrospective study, instead of obtaining informed consent from each patient, we are disclosing information about this study on the institution's website. In addition, this study does not include any animal experiments. This study is a retrospective observation of patients who have already completed standard treatment and have not been enrolled in any clinical trial registry.

DATA AVA I L A B I L I T Y S TAT E M E N T
None.